Novel Exposomics and Extracellular Vesicle Biomarkers to Unravel Gene-Environment Interactions and Mechanisms of Neurodegeneration in Parkinson's Disease
Abstract
Our goal is to characterize the synergistic contribution of the most common but incompletely penetrant genetic cause of Parkinson's disease (PD), LRRK2, and exposure to organic toxicants and neurotoxic metals suspected to be implicated in PD. Our Specific Aims (SA) are to SA-1: Use blood-borne extracellular vesicles (EVs) from the brain of PD patients to elucidate their exposome and metallome; and determine if individual toxicants or mixtures, independently or synergistically with LRRK2activation status, represent predictive biomarkers of disease. So far, we immunoisolated EVs from glial (GLAST) origin from plasma of healthy controls (n=65); sporadic PD (n=65); unaffected carriers LRRK2+/PD- (n=8); affected LRRK2+/PD+ (n=35)and are currently validating the isolation of neuronal-derived EVs (ATP1A3) before running our LRRK2 status, metallomics and exposomics analyses. SA-2: Identify GxE interactions relevant to PD-linked DA neurodegeneration and LRRK2 pathology. This first year, we amplified 6 induced pluripotent stem cell lines from LRRK2 PD patients and age/sex-matched controls. We differentiated these lines in either dopaminergic or astrocyte cultures and are currently screening different metal and organic toxicity on these cells. Our preliminary data suggest that control and PD LRRK2 astrocytes may have different capacity of eliminating excess of certain metals (Mn, As and Cu) via the EV pathway with potential neurotoxic consequences.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1219047
Entities
People
- Dianne Re
- Gary W. Miller
Organizations
- Columbia University